1. Field of the Invention
This invention relates to a novel conjugate having cytotoxicity and a process for the preparation thereof. More particularly, this invention relates to a novel conjugate having cytotoxicity comprising a constituent part consisting of an immunoglobulin capable of binding selectively to a particular antigen possessed by a cell to be killed (hereinafter referred to as target cell) or consisting of its fragment having a part which binds to such antigen and a constituent part consisting of a polymer carrying a cytotoxic substance linked thereto and a process for the preparation thereof. The conjugate having cytotoxicity obtained according to this invention is useful, for instance, as an antitumor agent which exerts an action on cancer cells selectively.
2. Description of the Prior Art
Many attempts have hitherto been made to bind cytotoxic substances of various kinds to an immunoglobulin, which is capable of binding selectively to a particular target cell, with the purpose of destroying certain kinds of cells selectively. For instance, a conjugate comprising an immunoglobulin having p-bis(2-chloroethyl)amino-L-phenylalanine, etc. linked thereto (Japanese Patent Application Laid-open No. 61640/76) a conjugate comprising an immunoglobulin having methotrexate linked thereto (Japanese Patent Application Laid-open No. 65829/81, a conjugate comprising an immunoglobulin having chlorambucil, etc. linked thereto (Japanese Patent Application Laid-open No. 65828/81), a conjugate comprising an immunoglobulin having mitomycin C, etc. linked thereto (Japanese Patent Application Laid-open No. 92325/80), and a conjugate comprising an immunoglobulin having daunomycin linked thereto (Japanese Patent Application Laid-open No. 144723/76) are publicly known.
These conjugates having cytotoxicity obtained according to the abovementioned methods are expected to bind selectively to a tumor cell and exert a toxic action on the tumor cell and accordingly may work as very useful drugs. However, in case where the cytotoxic substance is made to directly bind to the immunoglobulin, if the immunoglobulin has too much cytotoxic substance linked thereto, the activity of the immunoglobulin to recognize the antigen tends to become low, therefore, only a small amount of cytotoxic substance has to be bound to the immunoglobulin to avoid such problem.
There is, on the other hand, a probable assumption that the abovementioned problem can be improved upon when a polymer is used as an intermediate carrier of the cytotoxic substance. But a method described in Japanese Patent Application Laid-open No. 126281/76 presents another problem that, since the method includes the reaction in which a lot of cytotoxic substance is linked to the polymer carrier and another reaction in which the polymer-cytotoxic substance conjugate is linked to the immunoglobulin are both carried out at the same kinds of functional groups of the polymer, thus allowing the polymer carrier to bind to many immunoglobulins, the obtained conjugates not only fail to have a uniform structure and quality but also contain high molecular weight substances not useful as a therapeutic agent.